Closed loop control methods have been utilized in various biological and medical applications. Early examples include functional electrical stimulation in electromyography, and rate-responsive pacemakers in cardiology. Further examples include prosthetic device control, neural network stimulation, drug delivery, and studies of arrhythmia, fibrillation and defibrillation. Closed loop control for in vivo control of an insulin pump or of pancreatic stimulation is considered in U.S. Pat. No. 6,135,978. Another example is U.S. Pat. No. 6,819,956, where in vivo closed loop control of all or part of a nervous system is considered. These studies generally relate to controlling a high-level biological function (e.g., an organ-level function), and are often related to in vivo applications. This emphasis on in vivo application of closed loop control is understandable in view of the direct applicability of such control methods to alleviate various medical conditions arising from functional deficiency.
Although in vitro closed loop control typically does not have the direct medical applications of in vivo control, it has also been considered in the art. More specifically, U.S. Pat. No. 6,114,164 relates to a system for controlling an in vitro muscle tissue specimen in order to emulate an in vivo environment. A significant motivation for this work is that certain kinds of muscle tissue specimens (e.g., skeletal muscle specimens) do not develop normally in vitro without application of mechanical forces to the specimen. The closed loop control considered in U.S. Pat. No. 6,114,164 includes an applied mechanical stimulus and/or a measured mechanical response within the control loop, thereby providing automatic adjustment of the mechanical environment of the sample to an appropriate level.
However, many in vitro studies do not relate to organ-level or tissue-level functional parameters as in the preceding examples. Instead, lower-level cellular responses (e.g., a response voltage) to electrical stimulation are often of interest. Application of known closed loop control methods (e.g., as in U.S. Pat. No. 6,114,164) to such situations can be complicated by practical issues, such as the selection of an appropriate control algorithm, and distinguishing stimulus artifacts from the response of interest. Distinguishing artifacts from real responses can be especially difficult when the stimulus is electrical and the response is also electrical.
Accordingly, it would be an advance in the art to provide closed-loop control of an electrically active cell culture having an electrical cellular response to a change in an environmental parameter in order to measure the effect of that environmental parameter on the cell culture.